The single strongest genetic risk factor for Multiple Sclerosis (MS) is located within the major histocompatibility complex (MHC). Dr Morahan is using the scientific equivalent of a ‘fine-tooth comb’ to identify the genetic differences in a particular MHC region.
Certain versions of genes within this region have been known to increase susceptibility to MS for some time. However, the genetic story in this region is more complex than originally thought and recent evidence has shown it is likely that other factors are also at play.
One such factor may be the mechanism that switches genes on and off within tissues. Changes to these biological switches, controlled by the presence or absence of methylation on the DNA strand, may also increase susceptibility to MS by changing when the underlying genes are switched on or off.
In 2009 Dr Julia Morahan was awarded the prestigious Macquarie Group Foundation Australian–UK MS Society Exchange Fellowship to enable her to conduct research at the University of Oxford under the supervision of Professor George Ebers, one of the world’s foremost MS experts.
Dr Morahan has now completed her Fellowship and has chosen to return to Australia. She returns with a wealth of expertise and having made a significant contribution to our understanding of the role that genes play in a person's susceptibility to MS.
Dr Morahan has been researching the genetic basis of MS at Oxford’s renowned Wellcome Trust Centre for Excellence. She focussed on the genetic region which confers the highest risk of MS: the major histocompatibility complex or MHC class II.
“The work has focused on epigenetic changes, which refer to molecular differences that alter regulation of gene activity rather than altering the genes themselves,” explains Dr Morahan.
Epigenetic changes may result in the inappropriate silencing or activation of specific genes. They are often caused by differences in the number and position of chemical tags, known as methyl groups, on the DNA .
An ideal population for the examination of epigenetic differences is identical (monozygotic) twins, since they have identical DNA sequences but can differ in the amount and location of methylation.
Dr Morahan examined DNA methylation in pairs of identical twins ‘discordant’ for MS - where one individual in the twin pair has MS and the other twin does not. The twin pairs were identified via the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS).
The twin analysis identified different DNA methylation levels in discordant twins, particularly at two sites within the MHC class II region.
“While these DNA methylation differences support a potential role for epigenetic changes across the MHC region in the pathogenesis of MS, functional work now needs to be carried out to establish how they might impact gene regulation,” concludes Dr Morahan.
To date, this is the only study of methylation in MS that has covered the entire MHC region. The methods developed by Dr Morahan and her colleagues to conduct this analysis will enable further detailed investigation of larger samples of twins and wider groups of people with MS studied of longer time periods. This will lead to further insights into the molecular nature of epigenetic susceptibility to MS.
Dr Morahan has shared her findings with the MS research community through three publications directly resulting from her Fellowship project (see below). She also contributed to a further 13 publications in collaboration with her colleagues during her time in the UK.
Updated: 05 January, 2009